Diabetes is a disease in which the body does not produce or use insulin correctly. Insulin is a hormone that is required to convert sugar, starches and other food into energy needed for daily life. Insulin is produced by the beta cells in the islets of Langerhans in the pancreas. Partial or total loss of these cells will result in partial or total loss of insulin production.
There are two major types of diabetes.
Type 1 diabetes is an autoimmune disease in which the body actually fails to produce any insulin. Type 1 disease most often occurs in children and young adults but can develop at any age. Type 1 diabetes is characterized by total loss of beta cells so that the patient requires insulin by injection. Type 1 diabetes accounts for 10-15% of all diabetes. Type 1 diabetes is strongly associated with auto-antibodies and this association has become part of the definition/classification of type 1 diabetes. Type 1 diabetes is discussed in greater detail below.
Type 2 diabetes is a metabolic disorder resulting from the body's inability to make enough, or properly use, insulin. It is the most common form of the disease. Type 2 diabetes accounts for 85-90% of diabetes.
The definitions of type 1 and 2 diabetes, however, are changing slowly. Auto-antibodies are found in type 2 diabetes patients and type 2 diabetes is found in increasing numbers in children. As a result, the traditional view of type 1 and 2 diabetes as two different diseases both resulting in increased blood glucose levels is shifting to the view that there is a large grey zone with patients in between the two extremes. This view is important when evaluating the usefulness of different animal models.
Both genetic and environmental factors are believed to be involved in the development of type 1 (insulin dependent) diabetes (for reviews see Leslie et al., Diabetologia, 42, 3-14, 1999; and Schranz et al., Diab. Metab. Rev., 14, 3-29, 1998). The HLA Class II region is the strongest genetic component, but other genes and loci have been implicated as contributing to a genetic predisposition to the disease (reviewed in Schranz et al., 1998 (supra)). Monozygotic twin studies show only 20-30% concordance of type 1 diabetes indicating a significant contribution of environmental factors (Kyvik et al., BMJ, 311, 913-7, 1995). The role of environmental factors is also supported by the fact that more than 85% of new onset patients do not have a first degree relative with the disease (Dahlquist et al., Diabetologia, 32, 2-6, 1989).
Worldwide, there is a large variation in the incidence of type 1 diabetes, ranging from more than 40 patients per 100,000 in Finland to 1-2 cases per 100,000 in Japan (Onkamo et al., Diabetologia, 42, 1395-403, 1999). Seasonal variation in incidence rate, together with serological studies, have suggested viral infections as a major environmental risk factor for type 1 diabetes (for reviews see Jun et al., Diabetologia, 44, 271-285, 2001; Rayfield et al., Diab./Metab. Rev., 3, 925-57, 1987; and Vaarala et al., Diabetes Nutr. Metab., 12., 75-85, 1999). Congenital rubella virus infection (Menser et al., Lancet, i, 57-60, 1978) or different members in the enterovirus genus are most often implicated as an etiologic agents in diabetes development (Yoon, Do Viruses Play a Role in the Development of Insulin-dependent Diabetes?, 1991; Vaarala et al., 1999, (supra)). Signs of enterovirus infection during pregnancy (Dahlquist et al., Diabetologia, 32, 2-6, 1989; and Hyoty et al, Diabetes, 44, 652-657, 1995) and in some infants who developed islet cell autoantibodies and later type 1 diabetes (Lonnrot et al., Diabetes, 49, 1314-8, 2000) further supports this hypothesis. Both Coxsackie B and rota virus contain peptide sequences also found in the islet autoantigens glutamate decarboxylase (GAD65) (Kaufman et al., J. Clin. Invest., 89, 283, 292, 1992), the tyrosine-phosphatase like protein IA-2 (Honeyman et al., Diabetes, 49, 1319-1324, 2000) or proinsulin (Rudy et al., Mol. Med., 1, 625-33, 1995) suggesting that T lymphocytes recognizing viral antigens may potentially contribute to islet autoimmunity by cross-reactivity or molecular mimicry. Indeed, cross-reactive GAD65 and rubella virus peptides were recognized by T cells in type 1 diabetes patients (Ou et al., Diabetologia, 43, 750-62, 2000). Since T cell tests that predict type 1 diabetes are not yet available, standardized tests for GAD65, IA-2 or insulin autoantibodies are useful markers to predict type 1 diabetes (for a review see Gottleib et al., Arum. Rev. Med., 49, 391-405, 1998). Rota virus seroconversion was reported to be associated with increases in autoantibodies to GAD65, IA-2, and insulin suggesting that this virus infection may trigger or exacerbate islet autoimmunity in genetically susceptible children (Honeyman et al., 2000 (supra)). Coxsackie virus-induced diabetes in mice was also associated with the development of GAD antibodies (Gerling et al., Autoimmunity, 6 49-56,1991). It is still controversial, however, whether viruses cause beta cell destruction directly by a cytolytic infection in the islets or indirectly by initiating autoimmunity (Vreugdenhil et al., Clin. Infect. Dis., 31, 1025-31, 2000; and Kukreja et al., Cell Mol. Life Sci., 57, 534-41, 2000).
Rodents are well-known reservoirs and vectors for viruses causing disease in humans. Puumala virus causing Nephropathia Epidemica (Myhrman, Nordisk Medicinsk Tidskrift, 7, 739-794, 1934; and Niklasson et al., Lancet, 1, 1012-3, 1984) is one example of an important human pathogen carried by bank voles. It has been demonstrated that the incidence rate of human Nephropathia Epidemica correlates with the vole population density during the previous year (Niklasson et al., Am. J. Trop. Med. Hyg., 53, 134-40, 1995). More recently, statistical evidence suggests that type 1 diabetes in humans also tracks the 3- to 4-year population density cycles of the bank vole with a similar time lag (Niklasson et al., Emerg. Infect. Dis., 4, 187-93, 1998). It also was observed that a high frequency of bank voles trapped in the wild and kept in the laboratory for studies of stereotypic behavior (Schoenecker et al., Appl. Anim. Behav. Sci., 68. 349-357, 2000) develop symptoms of type 1 diabetes, i.e., polydipsia and glucosuria, at a high frequency.
Currently there are two main animal models of diabetes: the NOD (non obese diabetic) mouse and the BB (bio breeding) rat. Both models involve animals with insulin dependent diabetes. Both of the current models, however, fail to display important symptoms of human diabetes. The NOD mouse, for example, shows gender preferences that are opposite to the human disease (i.e., more females than males develop the disease), develops mild diabetes, requires a long time before developing ketoacidosis, and fails to develop autoantibodies to GAD65, 1A-2 or insulin. The disease is genetically controlled in the NOD mouse and the cleaner the animal, the higher the frequency of diabetes.
The BB rat is also no ideal. The animals have lymphopenia controlled by an autosomal mutation on chromosome 4 and the development of autoantibodies in inbred and specific pathogen free BB rats appears negligible. None of these BB rats develop diabetes in association with an infectious agent.
Thus, there is a need to develop an improved method for obtaining an animal model which displays the features of diabetes for both research and therapeutic purposes.